Trazodone

Trazodone
Systematic (IUPAC) name
2-(3-[4-(3-chlorophenyl)piperazin-1-yl]propyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one
Identifiers
CAS number 19794-93-5
ATC code N06AX05
PubChem CID 5533
IUPHAR ligand 213
DrugBank APRD00533
ChemSpider 5332
Chemical data
Formula C19H22ClN5O 
Mol. mass 371.864 g/mol
Pharmacokinetic data
Bioavailability High
Metabolism Hepatic
Half-life 3-6 hours
Excretion 20% feces,
80% urine
Therapeutic considerations
Pregnancy cat. C(US)
Legal status Unscheduled;
Rx only
Routes Oral
 YesY(what is this?)  (verify)

Trazodone (Desyrel, Oleptro, Beneficat, Deprax, Desirel, Molipaxin, Thombran, Trazorel, Trialodine, Trittico, Mesyrel) is an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) class. It is a phenylpiperazine compound. Trazodone also has anxiolytic, and hypnotic effects.[1] Trazodone has considerably less prominent anticholinergic (dry mouth, constipation, tachycardia) and sexual side effects than most of the tricyclic antidepressants (TCAs).

Contents

History

Trazodone was originally discovered and developed in Italy in the 1960s by Angelini research laboratories as a second-generation antidepressant. It was developed according to the mental pain hypothesis, which was postulated from studying patients and which proposes that major depression is associated with a decreased pain threshold.[2] Trazodone was patented and marketed in many countries all over the world. It was approved by the Food and Drug Administration (FDA) at the end of 1981.

Indications

Off-label and investigational uses

Pharmacology

Binding profile

Trazodone behaves as an antagonist at all of the following receptors except 5-HT1A where it acts as a partial agonist similarly to buspirone and tandospirone but with greater intrinsic activity in comparison:[16][17][18][19][20][21]

  • 5-HT1A receptor (Kd = 78 nM)
  • 5-HT2A receptor (Ki = 13 nM)
  • 5-HT2C receptor (Ki = 192 nM)
  • α1-adrenergic receptor (Kd = 39 nM)
  • α2-adrenergic receptor (Kd = 405 nM)
  • H1 receptor (Kd = 725 nM)

It is an inhibitor of the following transporters as well:[22]

The affinities listed are the means of selected values from the references included.

Clinical effects

Trazodone acts predominantly as a 5-HT2A receptor antagonist to mediate its therapeutic benefits against anxiety and depression.[23] Trazodone's inhibitory effects on serotonin reuptake and 5-HT2C receptors are relatively weak (~15-fold lower than 5-HT2A) and contribute only lightly to its overall effects.[23] Hence, trazodone does not have similar properties to selective serotonin reuptake inhibitors (SSRIs)[23] and is not particularly associated with increased appetite and weight gain, unlike other 5-HT2C antagonists like mirtazapine.[24][25] Moderate 5-HT1A partial agonism (6-fold lower than 5-HT2A) is likely to contribute to trazodone's antidepressant and anxiolytic actions to some extent as well.[20][21][26]

Trazodone's potent α1-adrenergic blockade (~3-fold lower relative to 5-HT2A) may cause some side effects like orthostatic hypotension and sedation.[27] Conversely, along with 5-HT2A antagonism, it may underlie trazodone's efficacy as a hypnotic. This seems plausible as trazodone's antihistamine activity is relatively weak and probably clinically insignificant; hence, it cannot explain trazodone's sleep-inducing/enhancing effects. Notably, trazodone lacks any affinity for muscarinic acetylcholine receptors and therefore does not produce anticholinergic side effects.

mCPP, a non-selective serotonin receptor agonist and serotonin releasing agent is a common active metabolite of trazodone, nefazodone, etoperidone, and mepiprazole, and it has been suggested that it may play a role in trazodone's therapeutic benefits.[28][29][30] However, scientific research has not supported this hypothesis and mCPP may even antagonize trazodone's efficacy as well as produce additional side effects.[31][32][33][34][35]

Pharmacokinetics

Trazodone is well absorbed after oral administration with mean peak blood levels obtained at approximately 1 hour after ingestion. Absorption is somewhat delayed and enhanced by food. The mean blood elimination half-life is biphasic: the first phase's half-life is 3–6 hours, and the following phase's half-life is 5–9 hours. The drug is extensively metabolized with 3 or 4 major metabolites having been identified in the human body, some of which such as mCPP[36] may contribute to the side effect profile of trazodone. mCPP has been shown to activate numerous serotonin receptors, including 5ht2c. Due to the short half-life of trazodone, if a dose is taken at night, mCPP would be present in the body during the following day, causing symptoms such as anorexia (behavioral symptoms), anxiety, hypolocomotion, headache, and depression. Approximately 70–75% of 14C-labelled trazodone was found to be excreted in the urine within 72 hours.[37] Trazodone is highly protein-bound.

Warnings

Precautions

Trazodone is metabolised by CYP3A4, a liver enzyme.[36] Inhibition of this enzyme by various other substances may delay its degradation, leading to high blood levels of trazodone. CYP3A4 may be inhibited by many other medications, herbs, and foods, and as such, trazodone may interact with these substances. One drug-food interaction is grapefruit juice. Drinking grapefruit juice is discouraged in patients taking trazodone. One glass of grapefruit juice occasionally is not likely to have this effect on most people, but drinking large amounts, or drinking it regularly is proven to affect trazodone's clearance.

The possibility of suicide in depressed patients remains during treatment and until significant remission occurs. Therefore, the number of tablets prescribed at any one time should take into account this possibility, and patients with suicidal ideation should never have access to large quantities of trazodone.

Trazodone has been reported to cause seizures in a small number of patients who took it concurrently with other anti seizure medications.[39]

While trazodone is not a true member of the SSRI class of antidepressants, it does still share many properties of the SSRIs, especially the possibility of discontinuation syndrome if the medication is stopped too quickly.[40] Care must therefore be taken when coming off the medication, usually by a gradual process of tapering down the dose over a period of time.

A person who abruptly stops taking trazodone, even in doses as low as 25 mg (common for use as a sleep aid for people with anxiety disorders), may experience adverse mental reactions such as emotional instability, depressed mood, and suicidal thoughts. Although such warnings may be included in printed materials supplied with the drug, physicians prescribing trazodone, particularly those who are not psychiatrists, might not give oral warnings.

Pregnancy and lactation

Side effects

The most common adverse reactions encountered are drowsiness, nausea/vomiting, headache and dry mouth. Adverse reactions reported include the following:

Behavioral

Drowsiness, fatigue, lethargy, psychomotor retardation, lightheadedness, dizziness, difficulty in concentration, confusion, memory loss, uncontrollable laughter, sex drive decrease, anger.

Neurological

Tremor, headache, ataxia, migraine, akathisia, muscle stiffness, slurred speech, slowed speech, vertigo, tinnitus, tingling of extremities, paresthesia, weakness, complex partial seizures, and rarely, impaired speech, muscle twitching, numbness, dystonia, euphoria, and Tardive dyskinesia.

Autonomic

Dry or numb mouth, blurred vision, priapism, diplopia, miosis, nasal congestion, constipation, sweating, urinary retention, increased urinary frequency and incontinence.

Cardiovascular

Hypotension, tachycardia, palpitations, shortness of breath, apnea, syncope, arrhythmias, prolonged P-R interval, atrial fibrillation, bradycardia, ventricular ectopic activity (including ventricular tachycardia), myocardial infarction, and cardiac arrest.

Rare side effects

Recent clinical studies in patients with pre-existing cardiac disease indicate that trazodone may be arrhythmogenic in some patients in that population. Arrhythmias identified include isolated PVC's, ventricular couplets, and in 2 patients short episodes (3 to 4 beats) of ventricular tachycardia. There have also been several post-marketing reports of arrhythmias in trazodone-treated patients who have pre-existing cardiac disease and in some patients who did not have pre-existing cardiac disease. Until the results of prospective studies are available, patients with pre-existing cardiac disease should be closely monitored, particularly for cardiac arrhythmias. Trazodone is not recommended for use during the initial recovery phase of myocardial infarction.

Priapism

Trazodone has rarely been associated with the occurrence of priapism. In approximately 33% of the cases reported, surgical intervention was required and, in a portion of these cases, permanent impairment of erectile function or impotence resulted.

Priapism is a potentially harmful medical condition in which the erect penis does not return to its flaccid state (despite the absence of both physical and psychological stimulation) within about four hours. It is often painful. Male patients with prolonged or inappropriate erections should immediately discontinue the drug and consult their physician. If the condition persists for more than 24 hours, it would be advisable for the treating physician to consult a urologist or appropriate specialist in order to decide on a management approach.

In women, a similar condition of persistent arousal can be caused and is called persistent genital arousal disorder.

Gastrointestinal

Nausea, vomiting, diarrhea, gastrointestinal discomfort, anorexia, increased appetite.

Liver

Rare cases of idiosyncratic hepatotoxicity have been observed, possibly due to the formation of reactive metabolites.[41]

Endocrine

Decrease and, more rarely, increase in libido, weight gain and loss, and rarely, menstrual irregularities, retrograde ejaculation and inhibition of ejaculation.

Elevated prolactin concentrations have been observed in patients taking trazodone.[42]

Allergic or toxic

Skin rash, itching, edema, and, rarely, hemolytic anemia, methemoglobinemia, liver enzyme alterations, obstructive jaundice, leukocytoclastic vasculitis, purpuric maculopapular eruptions, photosensitivity and fever.

Miscellaneous

Aching joints and muscles, hypersalivation, chest pain, hematuria, red, tired and itchy eyes. muscle twitches

Occupational hazards

Since trazodone may impair the mental and/or physical abilities required for performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned not to engage in such activities while impaired.

Laboratory tests

It is recommended that white blood cell and differential counts should be performed in patients who develop sore throat, fever, or other signs of infection or blood dyscrasia and trazodone should be discontinued if the white blood cell or absolute neutrophil count falls below normal.

Drug interactions

Trazodone may enhance the effects of alcohol, barbiturates and other CNS depressants; patients should be cautioned accordingly as trazodone with the combination of another CNS depressant, can result in extreme tiredness and dizziness.

Increased serum digoxin and phenytoin levels have been reported to occur in patients receiving trazodone concurrently with either of those 2 drugs. Little is known about the interaction between trazodone and general anesthetics; therefore, prior to elective surgery, trazodone should be discontinued for as long as clinically feasible.

Because it is not known whether an interaction will occur between trazodone and monoamine oxidase inhibitors (MAOI's), administration of trazodone should be initiated very cautiously with gradual increase in dosage as required, if an MAOI is given concomitantly or has been discontinued shortly before medication with trazodone is instituted.

Because of the absence of experience, concurrent administration of electroconvulsive therapy should be avoided.

Dosage

Treatment should be started with low initial doses of 25 to 50 mg daily in divided doses or in an evening single dose. The dose may be increased slowly to a maximum of 300 mg daily in ambulatory patients and to 600 mg daily in hospitalized patients. Geriatric and emaciated patients should begin with 25 mg daily; this dose may be slowly increased to 300 mg. The duration of treatment should be at least one month. A 50 mg dose is recommended when using Trazodone as a sleep aid.

Overdose

Symptoms

Overdose of trazodone may cause an increase in incidence or severity of any of the reported adverse reactions, e.g. excessive sedation. Death by deliberate or accidental overdosage has been reported.[43][44] However, trazodone is often used instead of tricyclic antidepressants because it is very rarely lethal in overdose. Depressed patients are therefore unlikely to successfully commit suicide with trazodone.[45]

Treatment

There is no specific antidote for trazodone. Management of overdosage should, therefore, be symptomatic and supportive. Any person suspected of having taken an overdosage should be evaluated at a hospital as soon as possible. Activated charcoal, gastric lavage, and forced diuresis may be useful in facilitating elimination of the drug.

Synthesis

Trazodone synthesis.png

Palazzo, G.; Silvestrini, B.; 1968, U.S. Patent 3,381,009.

See also

  • Etoperidone
  • Lubazodone
  • Nefazodone
  • Vilazodone

References

  1. ↑ Haria M, Fitton A, McTavish D (April 1994). "Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders". Drugs Aging 4 (4): 331–55. doi:10.2165/00002512-199404040-00006. PMID 8019056. 
  2. ↑ Silvestrini B (1989). "Trazodone: from the mental pain to the "dys-stress" hypothesis of depression". Clin Neuropharmacol 12 (Suppl 1): S4–10. PMID 2568177. 
  3. ↑ Nierenberg AA, Adler LA, Peselow E, Zornberg G, Rosenthal M (July 1994). "Trazodone for antidepressant-associated insomnia". Am J Psychiatry 151 (7): 1069–72. PMID 8010365. http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=8010365. 
  4. ↑ Kaynak H, Kaynak D, Gözükirmizi E, Guilleminault C (January 2004). "The effects of trazodone on sleep in patients treated with stimulant antidepressants". Sleep Med. 5 (1): 15–20. doi:10.1016/j.sleep.2003.06.006. PMID 14725822. http://linkinghub.elsevier.com/retrieve/pii/S1389945703002065. 
  5. ↑ Scharf MB, Sachais BA (September 1990). "Sleep laboratory evaluation of the effects and efficacy of trazodone in depressed insomniac patients". J Clin Psychiatry 51 (Suppl): 13–7. PMID 2211559. 
  6. ↑ Mavissakalian M, Perel J, Bowler K, Dealy R (June 1987). "Trazodone in the treatment of panic disorder and agoraphobia with panic attacks". Am J Psychiatry 144 (6): 785–7. PMID 3296792. http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=3296792. 
  7. ↑ Rickels K, Downing R, Schweizer E, Hassman H (November 1993). "Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam". Arch. Gen. Psychiatry 50 (11): 884–95. PMID 8215814. 
  8. ↑ Pope HG, Keck PE, McElroy SL, Hudson JI (August 1989). "A placebo-controlled study of trazodone in bulimia nervosa". J Clin Psychopharmacol 9 (4): 254–9. doi:10.1097/00004714-198908000-00004. PMID 2671058. 
  9. ↑ Prasad A (February 1985). "Efficacy of trazodone as an anti obsessional agent". Pharmacol. Biochem. Behav. 22 (2): 347–8. doi:10.1016/0091-3057(85)90403-4. PMID 3983224. http://linkinghub.elsevier.com/retrieve/pii/0091-3057(85)90403-4. 
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  19. ↑ Pälvimäki EP, Roth BL, Majasuo H, et al. (August 1996). "Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor". Psychopharmacology 126 (3): 234–40. doi:10.1007/BF02246453. PMID 8876023. http://link.springer.de/link/service/journals/00213/bibs/6126003/61260234.htm. 
  20. ↑ 20.0 20.1 Raffa RB, Shank RP, Vaught JL (1992). "Etoperidone, trazodone and MCPP: in vitro and in vivo identification of serotonin 5-HT1A (antagonistic) activity". Psychopharmacology 108 (3): 320–6. doi:10.1007/BF02245118. PMID 1387963. 
  21. ↑ 21.0 21.1 Odagaki Y, Toyoshima R, Yamauchi T (May 2005). "Trazodone and its active metabolite m-chlorophenylpiperazine as partial agonists at 5-HT1A receptors assessed by [35SGTPgammaS binding"]. Journal of Psychopharmacology (Oxford, England) 19 (3): 235–41. doi:10.1177/0269881105051526. PMID 15888508. http://jop.sagepub.com/cgi/pmidlookup?view=long&pmid=15888508. 
  22. ↑ Tatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". European Journal of Pharmacology 340 (2-3): 249–58. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821. http://linkinghub.elsevier.com/retrieve/pii/S0014-2999(97)01393-9. 
  23. ↑ 23.0 23.1 23.2 Marek GJ, McDougle CJ, Price LH, Seiden LS (1992). "A comparison of trazodone and fluoxetine: implications for a serotonergic mechanism of antidepressant action". Psychopharmacology 109 (1-2): 2–11. doi:10.1007/BF02245475. PMID 1365657. 
  24. ↑ Vanina Y, Podolskaya A, Sedky K, et al. (July 2002). "Body weight changes associated with psychopharmacology". Psychiatric Services (Washington, D.C.) 53 (7): 842–7. PMID 12096167. http://ps.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=12096167. 
  25. ↑ Watanabe N, Omori IM, Nakagawa A, et al. (January 2010). "Safety reporting and adverse-event profile of mirtazapine described in randomized controlled trials in comparison with other classes of antidepressants in the acute-phase treatment of adults with depression: systematic review and meta-analysis". CNS Drugs 24 (1): 35–53. doi:10.2165/11319480-000000000-00000. PMID 20030418. http://content.wkhealth.com/linkback/openurl?issn=1172-7047&volume=24&issue=1&spage=35. 
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  28. ↑ Melzacka M, Rurak A, Vetulani J (1980). "Preliminary study of the biotransformation of two new drugs, trazodone and etoperidone". Polish Journal of Pharmacology and Pharmacy 32 (4): 551–6. PMID 7255270. 
  29. ↑ Fong MH, Garattini S, Caccia S (October 1982). "1-m-Chlorophenylpiperazine is an active metabolite common to the psychotropic drugs trazodone, etoperidone and mepiprazole". The Journal of Pharmacy and Pharmacology 34 (10): 674–5. PMID 6128394. 
  30. ↑ Maes M, Westenberg H, Vandoolaeghe E, et al. (October 1997). "Effects of trazodone and fluoxetine in the treatment of major depression: therapeutic pharmacokinetic and pharmacodynamic interactions through formation of meta-chlorophenylpiperazine". Journal of Clinical Psychopharmacology 17 (5): 358–64. doi:10.1097/00004714-199710000-00004. PMID 9315986. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0271-0749&volume=17&issue=5&spage=358. 
  31. ↑ Mihara K, Yasui-Furukori N, Kondo T, et al. (August 2002). "Relationship between plasma concentrations of trazodone and its active metabolite, m-chlorophenylpiperazine, and its clinical effect in depressed patients". Therapeutic Drug Monitoring 24 (4): 563–6. doi:10.1097/00007691-200208000-00016. PMID 12142643. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0163-4356&volume=24&issue=4&spage=563. 
  32. ↑ Li AA, Marek GJ, Hand TH, Seiden LS (February 1990). "Antidepressant-like effects of trazodone on a behavioral screen are mediated by trazodone, not the metabolite m-chlorophenylpiperazine". European Journal of Pharmacology 177 (3): 137–44. doi:10.1016/0014-2999(90)90263-6. PMID 2311675. 
  33. ↑ Vetulani J, Sansone M, Baran L, Hano J (1984). "Opposite action of m-chlorophenylpiperazine on avoidance depression induced by trazodone and pimozide in CD-1 mice". Psychopharmacology 83 (2): 166–8. doi:10.1007/BF00429728. PMID 6431467. 
  34. ↑ Kast RE (2009). "Trazodone generates m-CPP: in 2008 risks from m-CPP might outweigh benefits of trazodone". The World Journal of Biological Psychiatry : the Official Journal of the World Federation of Societies of Biological Psychiatry 10 (4 Pt 2): 682–5. doi:10.1080/15622970902836022. PMID 19384678. http://informahealthcare.com/doi/abs/10.1080/15622970902836022. 
  35. ↑ Workman EA, Tellian F, Short D (May 1992). "Trazodone induction of migraine headache through mCPP". The American Journal of Psychiatry 149 (5): 712. PMID 1575270. 
  36. ↑ 36.0 36.1 Rotzinger S, Fang J, Baker GB (1 June 1998). "Trazodone is metabolized to m-chlorophenylpiperazine by CYP3A4 from human sources". Drug Metab. Dispos. 26 (6): 572–5. PMID 9616194. http://dmd.aspetjournals.org/cgi/content/full/26/6/572. 
  37. ↑ Jauch R, Kopitar Z, Prox A, Zimmer A (1976). "[Pharmacokinetics and metabolism of trazodone in man (author's transl)] [Pharmacokinetics and metabolism of trazodone in man (author's transl)]" (in German). Arzneimittelforschung 26 (11): 2084–9. PMID 1037253. 
  38. ↑ Webmd.com
  39. ↑ MentalHealth.com
  40. ↑ Warner CH, Bobo W, Warner C, Reid S, Rachal J (August 2006). "Antidepressant discontinuation syndrome". Am Fam Physician 74 (3): 449–56. PMID 16913164. http://www.aafp.org/afp/20060801/449.html. 
  41. ↑ Kalgutkar AS, Henne KR, Lame ME (June 2005). "Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4". Chem Biol Interact. 155 (1-2): 10–20. doi:10.1016/j.cbi.2005.03.036. PMID 15978881. http://linkinghub.elsevier.com/retrieve/pii/S0009-2797(05)00098-0. 
  42. ↑ Otani K, Yasui N, Kaneko S (June 1995). "Trazodone treatment increases plasma prolactin concentrations in depressed patients". Int Clin Psychopharmacol 10 (2): 115–7. doi:10.1097/00004850-199506000-00009. PMID 7673654. 
  43. ↑ Martínez MA, Ballesteros S, Sánchez de la Torre C, Almarza E (2005). "Investigation of a fatality due to trazodone poisoning: case report and literature review". J Anal Toxicol 29 (4): 262–8. PMID 15975258. http://openurl.ingenta.com/content/nlm?genre=article&issn=0146-4760&volume=29&issue=4&spage=262&aulast=Martínez. 
  44. ↑ de Meester A, Carbutti G, Gabriel L, Jacques JM (2001). "Fatal overdose with trazodone: case report and literature review". Acta Clin Belg 56 (4): 258–61. PMID 11603256. 
  45. ↑ Rakel RE (1987). "The greater safety of trazodone over tricyclic antidepressant agents: 5-year experience in the United States". Psychopathology 20 (Suppl 1): 57–63. doi:10.1159/000284524. PMID 3321131. 

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dsrd (o, p, m, p, a, d, s), sysi/, spvo

, drug(N5A/5B/5C/6A/6B/)
Hypnotics/Sedatives (N05C)
GABAA receptor
Ultrashort-acting
Methohexital • Thiamylal • Thiopental
Short/intermediate-
acting
Allobarbital • Amobarbital • Butabarbital • Butobarbital • Pentobarbital • Secobarbital • Talbutal
Long-acting
Barbital • Mephobarbital • Phenobarbital
Ungrouped
Cyclobarbital • Ethallobarbital • Heptabarbital • Hexobarbital • Proxibarbal • Reposal • Vinylbital • Vinbarbital
Short-acting
Brotizolam • Cinolazepam • Doxefazepam • Loprazolam • Midazolam • Triazolam
Intermediate-acting
Estazolam • Flunitrazepam • Lormetazepam • Nimetazepam • Temazepam
Long-acting
Flurazepam • Flutoprazepam • Nitrazepam • Quazepam
Dialkylphenols
Fospropofol • Propofol • Thymol
Nonbenzo-
diazepines
CL-218,872 • Eszopiclone • Indiplon • Lirequinil • Necopidem • Pazinaclone • ROD-188 • Saripidem • Suproclone • Suriclone • SX-3228 • U-89843A • U-90042 • Zaleplon • Zolpidem • Zopiclone
Piperidinediones
Glutethimide • Methyprylon • Pyrithyldione • Piperidione
Quinazolinones
Afloqualone • Cloroqualone • Diproqualone • Etaqualone • Mebroqualone • Mecloqualone • Methaqualone • Methylmethaqualone • Nitromethaqualone
Neuroactive
steroids
Acebrochol • Allopregnanolone • Alphadolone • Alphaxolone • Eltanolone • Ganaxolone • Hydroxydione • Minaxolone • Org 20599 • Org 21465 • Tetrahydrodeoxycorticosterone
Alpha-2 adrenergic
receptor
Alpha-adrenergic agonists
4-NEMD • Clonidine • Dexmedetomidine • Lofexidine • Medetomidine • Romifidine • Tizanidine • Xylazine
Melatonin receptor
Agomelatine • Melatonin • Ramelteon • Tasimelteon
Histamine receptor &
Acetylcholine receptor
Antihistamines &
Anticholinergics
Amitriptyline • Dimenhydrinate • Doxylamine • Hydroxyzine • Diphenhydramine • Bromodiphenhydramine • Carbinoxamine • Doxepin • Esmirtazapine • Orphenadrine • Mianserin • Mirtazapine • Phenyltoloxamine • Propiomazine • Pyrilamine • Scopolamine
5-HT2A &
α1-adrenergic
Selective 5-HT2A & α1-adrenergic antagonists
Etoperidone • Nefazodone • Niaprazine • Trazodone
GABAB receptor /
GHB receptor
GHB Type
1,4-Butanediol • Aceburic acid • GABOB • gamma-Hydroxybutyric acid • GBL • gamma-Valerolactone
Orexin receptors
Orexin antagonists
Almorexant • SB-334,867 • SB-408,124 • SB-649,868 • TCS-OX2-29
Other receptors/
ungrouped
Acetylglycinamide chloral hydrate • Chloral hydrate • Chloralodol • Dichloralphenazone • Paraldehyde • Petrichloral
Centalun • Ethchlorvynol • Ethinamate • Hexapropymate • Methylpentynol
Carbamates
Meprobamate • Carisoprodol • Tybamate • Methocarbamol • Procymate
Other
2-Methyl-2-butanol • Acecarbromal • Acetophenone • Apronal • Bromides • Bromisoval • Carbromal • Chloralose • Clomethiazole • Embutramide • Etomidate • Evoxine • Fenadiazole • Gaboxadol • Loreclezole • Mephenoxalone • Sulfonmethane • Trichloroethanol • Triclofos • Valerian • Valnoctamide
#WHO-EM. ‡Withdrawn from market. Clinical trials: †Phase III. §Never to phase III

mepr

dsrd (o, p, m, p, a, d, s), sysi/, spvo

, drug(N5A/5B/5C/6A/6B/)